The present invention is directed to novel methods for identifying small molecule drug lead compounds.
In response to the ever increasing demand for novel compounds useful in the effective treatment of various maladies, the medical research community has developed a number of different strategies for discovering and optimizing new therapeutic drugs. For the most part, these strategies are dependent upon molecular techniques that allow the identification of tightly binding ligands for a given biological target molecule. Once identified, these ligands may then carry out their therapeutic functions by activating, inhibiting or otherwise altering the activity of the molecular target to which they bind.
In one such strategy, new therapeutic drugs are identified by screening combinatorial libraries of synthetic small molecule compounds, determining which compound(s) have the highest probability of providing an effective therapeutic and then optimizing the therapeutic properties of the identified small molecule compound(s) by synthesizing structurally related analogs and analyzing them for binding to the target molecule (Gallop et al., J. Med. Chem. 37:1233-1251 (1994), Gordon et al., J. Med. Chem. 37:1385-1401 (1994), Czarnik and Ellman, Acc. Chem. Res. 29:112-170 (1996), Thompson and Ellman, Chem. Rev. 96:555-600 (1996) and Balkenhohl et al., Angew. Chem. Int. Ed. 35:2288-2337 (1996)). However, this process is not only time consuming and costly, it often does not provide for the successful identification of a small molecule compound having sufficient therapeutic potency for the desired application. For example, while the preparation and evaluation of combinatorial libraries of small molecules has proven somewhat useful for new drug discovery, the identification of small molecules for difficult molecular targets (e.g., such as those useful for blocking or otherwise taking part in protein-protein interactions) has not been particularly effective (Brown, Molecular Diversity 2:217-222 (1996)).
One issue that limits the success of combinatorial library approaches is that it is is possible to synthesize only a very small fraction of the possible number of small molecules. For example, greater than 1060 different small molecules having valid chemical structures and molecular weights under 600 daltons can be envisioned. However, even the most ambitious of small molecule combinatorial library efforts have been able to generate libraries of only tens to hundreds of millions of different compounds for testing. Therefore, combinatorial technology allows one to test only a very small subset of the possible small molecules, thereby resulting in a high probability that the most potent small molecule compounds will be missed. Thus, suitable small molecule compounds having the required availability, activity or chemical and/or structural properties often cannot be found. Moreover, even when such small molecule compounds are available, optimization of those compounds to identify an effective therapeutic often requires the synthesis of an extremely large number of structural analogs and/or prior knowledge of the structure of the molecular target for that compound. Furthermore, screening large combinatorial libraries of potential binding compounds to identify a lead compound for optimization can be difficult and time-consuming because each and every member of the library must be tested. It is evident, therefore, that novel methods for rapidly and efficiently identifying new small molecule drug leads are needed.
Living organisms evolve through a process that includes both (1) genetic recombination, where sexual reproduction acts to mix and recombine the attributes of the parent organisms to provide progeny having attributes of both parents, and (2) natural selection, where only those progeny that are sufficiently xe2x80x9cfitxe2x80x9d are capable of passing their attributes on to the next generation. Approaches that closely model the process by which organism evolve have previously been reported for identifying small molecules that bind to receptors and enzymes (Weber et al., Angew. Chem. Int. Ed. Engl. 34:2280-2282 (1995) and Singh et al., J. Am. Chem Soc. 118:1669-1676 (1996)). These approaches are based upon the mathematical method termed xe2x80x9cgenetic algorithmsxe2x80x9d (Holland, Sci. Am. 66-72 (1992)). Using genetic algorithms, a population of different compounds is screened to identify the compounds that bind to the receptor or enzyme (i.e., the xe2x80x9cfittestxe2x80x9d compounds). A population of progeny compounds is then prepared by recombining the building blocks that were used to prepare the xe2x80x9cfittestxe2x80x9d compounds. A screen is then performed to identify the compounds that bind to the target with the highest affinity, which are made up of the optimal building block combinations.
However, because the building blocks employed in the genetic algorithm approach are not preselected, one of two techniques are used to identify tight binding ligands: (1) extremely large populations of compounds must be screened and recombined, or (2) multiple rounds of screening and recombination are performed on relatively small populations where additional building blocks are gradually introduced through a process that is analogous to genetic mutation. In this second approach, many rounds of selection, recombination and building block introduction are required to identify the optimal building block combinations in analogy to the many rounds of selection, reproduction and mutation that are required in the evolution of living organisms. Thus, the use of genetic algorithms is currently limited because of the large amount of time required for compound preparation and screening, wherein the goal of new drug discovery is to identify a potent compound as quickly as possible.
Another recently reported approach for identifying high affinity ligands for molecular targets of interest is by determining structure-activity relationships from nuclear magnetic resonance analysis, i.e., xe2x80x9cSAR by NMRxe2x80x9d (Shuker et al., Science 274:1531-1534 (1996) and U.S. Pat. No. 5,698,401 by Fesik et al.). In this approach, the physical structure of a target protein is determined by NMR and then small molecule building blocks are identified that bind to the protein at nearby points on the protein surface. Adjacently binding small molecules are then coupled together with a linker in order to obtain compounds that bind to the target protein with higher affinity than the unlinked compounds alone. Thus, by having available the NMR structure of the target protein, the lengths of linkers for coupling two adjacently binding small molecules can be determined and small molecule ligands can be rationally designed. This approach has been useful for identifying compounds that bind to FK506 binding protein with a Kd=20 nM (Shuker et al., supra) and to stromelysin with a Kd=15 nM (Hajduk et al., J. Am. Chem. Soc. 119:5818-5827 (1997) and Hajduk et al., J. Am. Chem. Soc. 119:5828-5832 (1997)).
However, while the SAR by NMR method is powerful, it also has serious limitations. For example, the approach requires huge amounts of target protein ( greater than 200 mg) and this protein typically must be 15N-labeled so that it is useful for NMR studies. Moreover, the SAR by NMR approach usually requires that the target protein be soluble to  greater than 0.3 mM and have a molecular weight less than about 25-30 kDa. Additionally, the structure of the target protein is first resolved by NMR, a process which often can require a 6 to 12 month time commitment.
From the above, it is evident that there is a need for novel techniques useful for rapidly and efficiently identifying small molecule drug lead compounds that are capable of binding with high affinity to a molecular target of interest. We herein describe for the first time a method which is based upon pharmacophore recombination, wherein a population of small molecule pharmacophores are xe2x80x9cpre-selectedxe2x80x9d for the ability to bind to a molecular target and wherein the small molecule pharmacophores that bind with the highest affinity are then chemically linked in various combinations to provide a library of potential high affinity binding ligands. The library of potential binding ligands is then screened using a simple functional assay for the presence of one or more compounds that bind to the target molecule with very high affinity.
Applicants herein describe a molecular approach for rapidly and efficiently identifying small molecule ligands that are capable of binding to a target biological molecule with high affinity, wherein ligand compounds identified by the method are useful as new small molecule drug lead compounds. The herein described methods allow a library of only the most favorable compounds to be assayed for binding to a target biological molecule without the need for screening all possible small molecule compounds and combinations thereof for binding to the target as is required in standard combinatorial library approaches. More specifically, a library of candidate target binding fragments is assembled and subjected to a first screen or xe2x80x9cpre-screenedxe2x80x9d to identify a subset of that library that bind to a target biological molecule with or below a certain dissociation constant. Those candidate target binding fragments identified during this xe2x80x9cpre-screeningxe2x80x9d step as being capable of binding to the target biological molecule are then coupled or cross-linked in a variety of combinations using one or more linker elements to provide a library of potential high affinity binding ligands or candidate cross-linked target binding fragments, whose building blocks represent the small candidate target binding fragments having the highest affinity for the target biological molecule as identified in the xe2x80x9cpre-screeningxe2x80x9d step. The library of potential ligands or candidate cross-linked target binding fragments for binding to the target biological molecule is then screened a second time to identify those members that exhibit the lowest dissociation constant for binding to the target biological molecule. Because the library of candidate target binding fragment building blocks is initially xe2x80x9cpre-screenedxe2x80x9d to select for a much smaller set of the most favorable building blocks, the most productive building block and cross-linker combinations can be identified without the laborious task of screening all possible combinations of all building blocks coupled together by a set of linkers. The process of identifying high affinity drug lead compounds is therefore, greatly expedited.
With regard to the above, one embodiment of the present invention is directed to a method for identifying drug lead compounds that bind to a biological target molecule of interest, wherein the method comprises the steps of:
(a) Assembling a library of candidate target binding fragments (CTBF) capable of being chemically cross-linked by a cross-linker element to provide candidate cross-linked target binding fragments for binding to the target biological molecule;
(b) screening the library of candidate target binding fragments to identify at least first and second candidate target binding fragments which bind to the target biological molecule;
(c) chemically cross-linking the at least first and second candidate target binding fragments or structurally related analogs thereof with a cross-linker element to provide a library of candidate cross-linked target binding fragments for binding to the target biological molecule; and
(d) screening the library obtained in (c) to identify a drug lead compound that binds to the target biological molecule.
In various preferred embodiments, the library of candidate target binding fragments may comprise compounds of less than 500 daltons, may comprise simple aldehydes, amines, amides, carbamates, ureidos, sulfonamides, alcohols, carboxylic acids, thiols, aryl halides, alkenes, alkynes, ketones, ethers and/or oximes and/or may bind to the target biological molecule with a Kd of 10 mM or lower. In a particularly preferred embodiment, the library or candidate target binding fragments may comprise oxime compounds, wherein the structurally related aldehyde analogs of those oxime compounds are capable of being chemically cross-linked via an O,Oxe2x80x2-diamino-alkanediol cross-linker. Target biological molecules that find use in the described methods include, for example, proteins, nucleic acids and saccharides, preferably proteins. Preferred TBM""s include human or human pathogen proteins, especially enzymes, human hormones, human receptors and fragments thereof. These TBM""s may all contain atoms of naturally occuring isotopic abundance.
In other preferred embodiments, the library of candidate cross-linked target binding fragments comprises candidate cross-linked target binding fragments of less than about 1000 daltons, that may be homo- or heterodimeric having a Kd for the TBM of from about 500 xcexcM to about 500 nM or lower.
Another embodiment of the present invention is directed to a method for inhibiting the interaction between first and second biological molecules, wherein the method comprises the step of contacting a system comprising both the first and second biological molecules with a binding inhibitory amount of a candidate cross-linked target binding fragment identified by the above described method, wherein the candidate cross-linked target binding fragment binds to one of the first or second biological molecules and inhibits their ability to interact.
A further embodiment of the present invention is directed to a drug lead compound made by the the method described herein, where the compound is represented by the formula: 
where
TBFm represents a first TBF selected from step (d);
TBFn represents a second TBF selected from step (d);
TBFm-part A and B represent TBFm from step (d) where each fragment is bonded to a single atom in LG3;
TBFn-part C and D represent TBFn from step (d) where each fragment is bonded to a single atom in LG4;
XL represents a cross-linker of the formula
xe2x80x94(C0-C2-alkyl-L1-L2-L3-L4-L5-C0-C2-alkyl)-;
LG1 and LG2 are linking groups independently selected from the group xe2x80x94C(Ra)xe2x95x90Nxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94Nxe2x95x90C(Ra)xe2x80x94, xe2x80x94CH2xe2x80x94N(Ra)xe2x80x94, xe2x80x94N(Ra)xe2x80x94CH2xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94N(Ra)xe2x80x94, xe2x80x94N(Ra)xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94N(Ra)xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94N(Ra)xe2x80x94, xe2x80x94N(Ra)xe2x80x94C(xe2x95x90O)xe2x80x94N(Rb)xe2x80x94, xe2x80x94N(Ra)xe2x80x94C(xe2x95x90O)xe2x80x94N(Rb)xe2x80x94, xe2x80x94SO2xe2x80x94N(Ra)xe2x80x94 and xe2x80x94N(Ra)xe2x80x94SO2xe2x80x94;
LG3 and LG4 are linking groups independently selected from the group  greater than Cxe2x95x90Nxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94Nxe2x95x90C less than , xe2x80x94CH2xe2x80x94N less than ,  greater than Nxe2x80x94CH2xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94N less than ,  greater than Nxe2x80x94C(xe2x95x90O)xe2x80x94,  greater than Nxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94N less than ,  greater than Nxe2x80x94C(xe2x95x90O)xe2x80x94N(Rb)xe2x80x94, xe2x80x94N(Ra)xe2x80x94C(xe2x95x90O)xe2x80x94N less than , xe2x80x94SO2xe2x80x94N less than  and  greater than Nxe2x80x94SO2xe2x80x94, where  less than  and  greater than  represent two bonds linking CTBFxe2x80x94 part A, B, C, or D to the single N or C atom in LG3 or LG4;
Ra and Rb are independently selected from the group hydrogen, C1-C10-alkyl, C0-C10-alkyl-C6-C10-aryl, C6-C10-aryl-C0-C10-alkyl, C0-C10-alkylheterocycle -C0-C10-alkyl, C1-C6-alkyl-NH-C1-C6-alkyl, C0-C10-alkyl-O-C0-C10-alkyl, C0-C10-alkyl-C(xe2x95x90O)-C0-C10-alkyl, C0-C10-alkyl-NHxe2x80x94C(xe2x95x90O)-C0-C10-alkyl, C0-C10-alkyl-Oxe2x80x94C(xe2x95x90O)-C0-C10-alkyl, where any alkyl, aryl or heterocycle is optionally substituted with C1-C10-alkyl, C1-C10-alkoxy, C6-C10-aryl, C6-C10-aryloxy, halo (F, Cl, Br, I), hydroxy, carboxy, amino, nitro and S(O)0-3;
TBFm, TBFn, TBFm-part A, TBFm-part B, TBFn-part C and TBFn-part D are each independently represented by formula I
-A-(Cycle 1)-B-(Cycle 2)-Exe2x80x83xe2x80x83(I)
Where
Cycle 1 and Cycle 2 are independently present or absent and are selected from a mono-, bi-, or tricyclic saturated, unsaturated, or aromatic ring, each ring having 5, 6 or 7 atoms in the ring where the ring atoms are carbon or from 1-4 heteroatoms selected from; nitrogen, oxygen, and sulfur, and where any sulfur ring atom may optionally be oxidized and any carbon ring atom may form a double bond with O, NRn and CR1R1xe2x80x2, each ring nitrogen may be substituted with Rn and any ring carbon may be substituted with Rd;
A and B are independently selected from 
xe2x80x83where:
L1 is absent or may be selected from oxo (O), S(O)s, C(xe2x95x90O), C(xe2x95x90Nxe2x80x94Rn), C(xe2x95x90CR1R1xe2x80x2), C(R1R1xe2x80x2), C(R1), C, het, N(Rn) or N;
L2 is absent or may be selected from oxo (O), S(O)s, C(xe2x95x90O), C(xe2x95x90Nxe2x80x94Rn), C(xe2x95x90CR2R2xe2x80x2), C(R2R2xe2x80x2), C(R2), C, het, N(Rn) or N;
L3 is absent or may be selected from oxo (O), S(O)s, C(xe2x95x90O), C(xe2x95x90Nxe2x80x94Rn), C(xe2x95x90CR3R3xe2x80x2), C(R3R3xe2x80x2), C(R3), C, het, N(Rn) or N;
L4 is absent or may be selected from oxo (O), S(O)s, C(xe2x95x90O), C(xe2x95x90Nxe2x80x94Rn), C(xe2x95x90CR4R4xe2x80x2), C(R4R4xe2x80x2), C(R4), C, NRn or N; and
L5 is absent or may be selected from oxo (O), S(O)s, C(xe2x95x90O), C(xe2x95x90Nxe2x80x94Rn), C(xe2x95x90CR5R5xe2x80x2), C(R5R5xe2x80x2), C(R5), C, NRn or N;
R1, R1xe2x80x2, R2, R2xe2x80x2, R3, R3xe2x80x2, R4, R4xe2x80x2, R5 and R5xe2x80x2each are independently selected from Ra, Raxe2x80x2, Rc and U-Q-V-W; where s is 0-2
Optionally, each R1-R5 or NRn together with any other R1-R5 or NRn may form a mono-, bi-, or tricyclic saturated, unsaturated, or aromatic ring, each ring being a homo- or heterocycle having 5, 6 or 7 atoms in the ring, optionally each ring containing 1-4 heteroatoms selected from N, O and S where any ring carbon or sulfur atom may optionally be oxidized, each ring nitrogen optionally substituted with Rn and each ring carbon optionally substituted with Rd;
E is -L1-L2L3-Ra;
Ra is selected from the group; hydrogen, halo(F, Cl, Br, I), halo(F, Cl, Br, I)xe2x80x94C1-C11alkyl, halo(F, Cl, Br, I)-C1-C11alkoxy, hydroxy-C1-C11alkyl, cyano, isocyanate, carboxy-C0-C11alkyl, amino, C0-C11alkyl-amino-(C1-C8alkyl), C0-C11alkyl-amino-di-(C1-C8alkyl), aminocarbonyl, C1-C11alkylcarbonylamino, carboxamido, carbamoyl, carbamoyloxy, formyl, formyloxy, azido, nitro, hydrazide, hydroxamic acid, imidazoyl, ureido, thioureido, thiocyanato, hydroxy, C1-C6alkoxy, mercapto, sulfonamido, het, phenoxy, phenyl, benzyl, benzyloxy, benzamido, tosyl, morpholino, morpholinyl, piperazinyl, piperidinyl, pyrrolinyl. imidazolyl and indolyl;
Raxe2x80x2is selected from the group of C0-C10alkyl-Q-C0-C6alkyl, C0-C10alkenyl-Q-C0-C6alkyl, C0-C10alkynyl-Q-C0-C6alkyl, C3-C11cycloalkyl-Q-C0-C6alkyl, C3-C10cycloalkenyl-Q-C0-C6alkyl, C1-C6alkyl-C6-C12aryl-Q-C0-C6alkyl, C6-C10aryl-C1-C6alkyl-Q-C0-C6alkyl, C0-C6alkyl-het-Q-C0-C6alkyl, C0-C6alkyl-Q-het-C0-C6alkyl, het-C0-C6alkyl-Q-C0-C6alkyl, C0-C6alkyl-Q-C6-C12aryl and Q-C1-C6alky, where any aryl or het is optionally substituted with 1-3 Rd and any alkyl, alkenyl or alkynyl is optionally substituted with 1-3 Ra;
Ra and Raxe2x80x2may join to form a 3-7 member homocyclic ring substituted with 1-3 Ra;
Rc is selected from hydrogen and substituted or unsubstituted; amino, O-C1-C8alkyl, amino-(C1-C8alkyl), amino-di-(C1-C8alkyl), C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C11cycloalkyl, C3-C10cycloalkenyl, C1-C6alkyl-C6-C12aryl, C6-C10aryl-C1-C6alkyl, C1-C6alkyl-het, het-C1-C6alkyl, C6-C12aryl and het, where the substitutes on any alkyl, alkenyl or alkynyl are 1-3 Ra and the substituents on any aryl or het are 1-3 Rd;
Rd is selected from Rh and Rp;
RH is selected from the group OH, OCF3, OR3, SRm, halo(F, Cl, Br, I), CN, isocyanate, NO2, CF3, C0-C6alkyl-NRnRnxe2x80x2, C0-C6alkyl-C(xe2x95x90O)xe2x80x94NRnRnxe2x80x2, C0-C6alkyl-C(xe2x95x90O)xe2x80x94Ra, C1-C8alkyl, C1-C8alkoxy, C2-C8alkenyl, C2-C8alkynyl, C3-C6cycloalkyl, C3-C6cycloalkenyl, C1-C6alkyl-phenyl, phenyl-C1-C6alkyl, C1-C6alkyloxycarbonylamino, C1-C6alkyloxycarbonyl-C0-C6alkyl, phenyl-C0-C6alkyloxy, C1-C6alkyl-het, het-C1-C6alkyl, SO2-het, O-C6-C12aryl, SO2-C6-C12aryl, SO2-C1-C6alkyl and het, where any alkyl, alkenyl or alkynyl may optionally be substituted with 1-3 groups selected from OH, halo(F, Cl, Br, I), nitro, amino and aminocarbonyl, where the substituents on any aryl or het are 1-2 hydroxy, halo(F, Cl, Br, I), CF3, C1-C6alkyl, C1-C6 alkoxy, nitro and amino;
Rm is selected from hydrogen, S-C1-C6alkyl, C(xe2x95x90O)-C1-C6alkyl, C(xe2x95x90O)xe2x80x94NRnRnxe2x80x2, C1-C6alkyl, halo(F, Cl, Br, I)-C1-C6alkyl, benzyl and phenyl;
Rn is selected from the group RC, OH, OCF3, ORo, CN, isocyanate, NHxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94Rc, NHxe2x80x94C(xe2x95x90O)xe2x80x94Rc, NHxe2x80x94C(xe2x95x90O)xe2x80x94NHRc, NHxe2x80x94SO2xe2x80x94Rs, NHxe2x80x94SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94Rc, NHxe2x80x94C(xe2x95x90O)xe2x80x94NH-SO2xe2x80x94Rs, C(xe2x95x90O)xe2x80x94Oxe2x80x94Ro, C(xe2x95x90O)xe2x80x94Rc, C(xe2x95x90O)xe2x80x94NHRc, C(xe2x95x90O)xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94Ro, C(xe2x95x90O)xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94Rc, C(xe2x95x90O)xe2x80x94NHxe2x80x94SO2xe2x80x94Rs, C(xe2x95x90O)xe2x80x94NHxe2x80x94SO2xe2x80x94NHRc, SO2xe2x80x94Rs, SO2xe2x80x94Oxe2x80x94Ro, SO2xe2x80x94N(Rc)2, SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94Ro, SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94Ro and SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94Rc;
Ro is selected from hydrogen and substituted or unsubstituted C1-C6alkyl, C0-C6alkyl-C6-C10aryl, C1-C6alkylcarbonyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl and benzoyl, where the substitutes on any alkyl are 1-3 Ra and the substituents on any aryl are 1-3 Rp;
Rp is selected from the group; OH, COOH, COH, NH2, C0-C6alkyl, halo(F, Cl. Br, I), CN, isocyanate, ORo, SRm, SORo, NO2, CF3, Rc, NRnRnxe2x80x2, N(Rn)xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94Ro, N(Rn)xe2x80x94C(xe2x95x90O)xe2x80x94Rc, SO2xe2x80x94Rs, C0-C6alkyl-SO2xe2x80x94Rs, C0-C6alkyl-SO2xe2x80x94NRnRnxe2x80x2, C(xe2x95x90O)xe2x80x94Rc, Oxe2x80x94C(xe2x95x90O)xe2x80x94Rc, C(xe2x95x90O)xe2x80x94Oxe2x80x94Ro and C(xe2x95x90O)xe2x80x94NRnRnxe2x80x2, where the substitutes on any alkyl, alkenyl or alkynyl are 1-3 Ra and the substituents on any aryl or het are 1-3 Rd;
Rs is a substituted or unsubstituted group selected from; C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl, C3-C6cycloalkenyl C0-C6alkyl- C6-C10aryl, C6-C10aryl-C0-C6alkyl, C0-C6alkyl-het and het-C0-C6alkyl, where the substitutes on any alkyl, alkenyl or alkynyl are 1-3 Ra and the substituents on any aryl or het are 1-3 Rd;
het is any mono-, bi-, or tricyclic saturated, unsaturated, or aromatic ring where at least one ring is a 5-, 6- or 7-membered ring containing from one to four heteroatoms selected from the group nitrogen, oxygen, and sulfur, the 5-membered ring having from 0 to 2 double bonds and the 6- or 7-membered ring having from 0 to 3 double bonds and where any carbon or sulfur atoms in the ring may optionally be oxidized, and where any nitrogen heteroatom may optionally be quaternized and where any ring may contain from 0-3 Rd;
U is an optionally substituted bivalent radical selected from the group; C1-C6alkyl, C0-C6alkyl-Q, C2-C6alkenyl-Q, and C2-C6alkynyl-Q, where the substitutes on any alkyl, alkenyl or alkynyl are 1-3 Ra;
Q is absent or is selected from the group; xe2x80x94Oxe2x80x94, xe2x80x94S(O)sxe2x80x94, xe2x80x94SO2xe2x80x94N(Rn)xe2x80x94, xe2x80x94N(Rn)xe2x80x94, xe2x80x94N(Rn)xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94N(Rn)xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94N(Rn)xe2x80x94SO2xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, -het-,xe2x80x94C(xe2x95x90O)xe2x80x94N(Rn)xe2x80x94, xe2x80x94PO(ORc)Oxe2x80x94 and xe2x80x94P(O)Oxe2x80x94, where s is 0-2 and the heterocyclic ring is substituted with 0-3 Rh;
V is absent or is an optionally substituted bivalent group selected from C1-C6alkyl, C3-C8cycloalkyl, C0-C6alkyl-C6-C10aryl, and C0-C6alky-het, where the substitutes on any alkyl are 1-3 Ra and the substituents on any aryl or het are 1-3 Rd;
W is selected from the group; hydrogen, xe2x80x94ORo, xe2x80x94SRm, xe2x80x94NRnRnxe2x80x2, xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94Ro, xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NRnRnxe2x80x2, xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94Rc, xe2x80x94NHxe2x80x94SO2xe2x80x94Rs, xe2x80x94NHxe2x80x94SO2xe2x80x94NRnRnxe2x80x2, xe2x80x94NHxe2x80x94SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94Rc, xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94SO2xe2x80x94Rs, xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94Ro, xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94Rc, xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NRnRnxe2x80x2, xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94SO2xe2x80x94Rs, xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94SO2xe2x80x94NRnRnxe2x80x2, xe2x80x94C(xe2x95x90S)xe2x80x94NRnRnxe2x80x2, xe2x80x94SO2xe2x80x94Rs, xe2x80x94SO2xe2x80x94Oxe2x80x94Ro, xe2x80x94SO2xe2x80x94NRnRnxe2x80x2, xe2x80x94SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94Ro, xe2x80x94SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NRnRnxe2x80x2, xe2x80x94SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94Rc, xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94NRnRnxe2x80x2, xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94RnRnxe2x80x2, xe2x80x94SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94Rc, xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94NRnRnxe2x80x2, xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94Rc, xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94Rc, xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94SO2xe2x80x94Rs and xe2x80x94Oxe2x80x94SO2xe2x80x94Rs;
Optionally, TBFm-part A together with TBFm-part B and TBFn-part C together with TBFn-part D may independently form Cycle 1 substituted with -B-(Cycle 2)-E.
A drug lead precursor or intermediate of this invention is represented by C0-C2-alkyl-L1-L2-L3-L4-L5-C0-C2-alkyl where L1 through L5 are defined above. Additional embodiments of the present invention will become evident to the ordinarily skilled artisan upon a review of the present specification.